Search results for: Erturk Alper

Authors: Şule Yanık, Emel Ertürk-Mustul, Zerrin Turan, Hasan Gürgür

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It is known that there are policies that will support the early special education (ESE) for children requiring special care including the children with hearing loss (CHL) in many countries that give importance to early childhood (0-6 years) education, accordingly ESE services have been gradually increasing and these services provide positive contributions to the child and family. These services begin with medical diagnostics, provision of the use of assistive technologies for hearing and the orientation of children towards early education program (EEP) for the CHL. In 0-3 years of age EEP, education and support services are provided to the children and their families. In 3-6 years of age, children are supported in a pre-school education program (PSE) in which their peers and teachers are present. Therefore, the children with hearing loss and their families are going through a series of medical, educational and social transition process after diagnosed with hearing loss. Depending on their age and development, CHL also go through a transition period from hospital to home, from home to EEP and from EEP to PSE. It is seen that there is no legal regulation regarding the transition process in Turkey and hence different processes have been carried out in the transition process from EEP to PSE. The aim of this study is to reveal the problems confronted by the CHL during the transition period from EEP to PSE and the solution proposals for these problems. In this study, a document review was made by reviewing the national and international studies about transition processes of the CHL in Turkey from EEP to PSE. Accordingly, in the study carried out in two stages, firstly, a review of the body of literature was performed by creating key words related to the subject. Secondly, the problems confronted by the CHL in Turkey during the transition period from EEP to PSE and the solution proposals for these problems were demonstrated by analyzing the obtained data. According to the body of literature, it is seen that there are no laws concerning the transition processes of the children who require special care including the CHL in Turkey from EEP (sending) to PSE (receiving), and correspondingly numerous problems have been experienced during the transition period. It seems that the EEP adopts family-centered approaches for strengthening the families of the CHL. However, PSE program aims to prepare the children to school life by focusing on their social and academical development rather with the adoption of children-centered approaches. Therefore, while the families feel an inseparable part of the team in EEP, they indicated that they felt like a stranger in the school team after their children have started to PSE. Therefore, families find the transition processes worrisome and state that they are not satisfied with the process. We discovered that in the process of transition from EEP to PSE, families are not informed, there is a limited number of PSE options available, children cannot adapt to the new educational environment and cannot benefit from the existing PSE.

Keywords: early education program, early special education, children with hearing loss, transition

Procedia PDF Downloads 113

Authors: Alper Cumhur, Hasan Baylavlı, Eren Gödek

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Use of superplasticity chemical admixtures in concrete production is widespread all over the world and has become almost inevitable. Super-plasticizers (SPA), extend the setting time of concrete by adsorbing onto cement particles and provide concrete to preserve its fresh state workability properties. Hyper-plasticizers (HPA), as a special type of superplasticizer, provide the production of qualified concretes by increasing the workability properties of concrete, effectively. However, compatibility of cement with super and hyper-plasticizers is quite important for achieving efficient workability in order to produce qualified concretes. In 2011, the EN 197-1 standard is edited and cement classifications were updated. In this study, the compatibility of hyper-plasticizer and CEM I SR0 type sulphate resisting cement (SRC) that firstly classified in EN 197-1 is investigated. Within the scope of the experimental studies, a reference cement mortar was designed with a water/cement ratio of 0.50 confirming to EN 196-1. Fresh unit density of mortar was measured and spread diameters (at 0, 60, 120 min after mix preparation) and setting time of reference mortar were determined with flow table and Vicat tests, respectively. Three mortars are being re-prepared with using both super and hyper-plasticizer confirming to ASTM C494 by 0.50, 0.75 and 1.00% of cement weight. Fresh unit densities, spread diameters and setting times of super and hyper plasticizer added mortars (SPM, HPM) will be determined. Theoretical air-entrainment values of both SPMs and HPMs will be calculated by taking the differences between the densities of plasticizer added mortars and reference mortar. The flow table and Vicat tests are going to be repeated to these mortars and results will be compared. In conclusion, compatibility of SRC with SPA and HPA will be investigated. It is expected that optimum dosages of SPA and HPA will be determined for providing the required workability and setting conditions of SRC mortars, and the advantages/disadvantages of both SPA and HPA will be discussed.

Keywords: CEM I SR0, hyper-plasticizer, setting time, sulphate resisting cement, super-plasticizer, workability

Procedia PDF Downloads 181

Authors: Abbas Ali Husseini, Ali Mohammad Yazdani, Fatemeh Ghadiri, Alper Şişman

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We developed a microchip device that uses surface acoustic waves for rapid lysis of low level of cell samples. The device incorporates sharp-edge glass microparticles for improved performance. We optimized the lysis conditions for high efficiency and evaluated the device's feasibility for point-of-care applications. The microchip contains a 13-finger pair interdigital transducer with a 30-degree focused angle. It generates high-intensity acoustic beams that converge 6 mm away. The microchip operates at a frequency of 16 MHz, exciting Rayleigh waves with a 250 µm wavelength on the LiNbO3 substrate. Cell lysis occurs when Candida albicans cells and glass particles are placed within the focal area. The high-intensity surface acoustic waves induce centrifugal forces on the cells and glass particles, resulting in cell lysis through lateral forces from the sharp-edge glass particles. We conducted 42 pilot cell lysis experiments to optimize the surface acoustic wave-induced streaming. We varied electrical power, droplet volume, glass particle size, concentration, and lysis time. A regression machine-learning model determined the impact of each parameter on lysis efficiency. Based on these findings, we predicted optimal conditions: electrical signal of 2.5 W, sample volume of 20 µl, glass particle size below 10 µm, concentration of 0.2 µg, and a 5-minute lysis period. Downstream analysis successfully amplified a DNA target fragment directly from the lysate. The study presents an efficient microchip-based cell lysis method employing acoustic streaming and microparticle collisions within microdroplets. Integration of a surface acoustic wave-based lysis chip with an isothermal amplification method enables swift point-of-care applications.

Keywords: cell lysis, surface acoustic wave, micro-glass particle, droplet

Procedia PDF Downloads 52

Authors: Fulya Asena Uluç, Ehsan Tuzcuoğlu, Songül Bayraktar, Burak Koca, Alper Gürarslan

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Microplastics are contaminants that are widely distributed in the environment with a detrimental ecological effect. Besides this, recent research has proved the existence of microplastics in human blood and organs. Microplastics in the environment can be divided into two main categories: primary and secondary microplastics. Primary microplastics are plastics that are released into the environment as microscopic particles. On the other hand, secondary microplastics are the smaller particles that are shed as a result of the consumption of synthetic materials in textile products as well as other products. Textiles are the main source of microplastic contamination in aquatic ecosystems. Laundry of synthetic textiles (34.8%) accounts for an average annual discharge of 3.2 million tons of primary microplastics into the environment. Recently, microfiber shedding from laundry research has gained traction. However, no comprehensive study was conducted from the standpoint of rinsing parameters during laundry to analyze microfiber shedding. The purpose of the present study is to quantify microfiber shedding from fabric under different rinsing conditions and determine the effective rinsing parameters on microfiber release in a laundry environment. In this regard, a parametric study is carried out to investigate the key factors affecting the microfiber release from a front-load washing machine. These parameters are the amount of water used during the rinsing step and the spinning speed at the end of the washing cycle. Minitab statistical program is used to create a design of the experiment (DOE) and analyze the experimental results. Tests are repeated twice and besides the controlled parameters, other washing parameters are kept constant in the washing algorithm. At the end of each cycle, released microfibers are collected via a custom-made filtration system and weighted with precision balance. The results showed that by increasing the water amount during the rinsing step, the amount of microplastic released from the washing machine increased drastically. Also, the parametric study revealed that increasing the spinning speed results in an increase in the microfiber release from textiles.

Keywords: front load, laundry, microfiber, microfiber release, microfiber shedding, microplastic, pollution, rinsing parameters, sustainability, washing parameters, washing machine

Procedia PDF Downloads 64

Authors: Adil Mustafa, Ahmet Erten, Alper Kiraz, Melikhan Tanyeri

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Work presented here is based on a novel experimental technique used to hydrodynamically trap oil microdroplets inside a microfluidic chip at the junction of microchannels known as stagnation point. Hydrodynamic trapping has been recently used to trap and manipulate a number of particles starting from microbeads to DNA and single cells. Benzyl Benzoate (BB) is used as droplet material. The microdroplets are trapped individually at stagnation point and their dissolution was observed. Experiments are performed for two concentrations (10mM or 10µM) of AOT surfactant (Docusate Sodium Salt) and two flow rates for each case. Moreover, experimental data is compared with Zhang-Yang-Mao (ZYM) model which studies dissolution of liquid microdroplets in the presence of a host fluid experiencing extensional creeping flow. Industrial processes like polymer blending systems in which heat or mass transport occurs experience extensional flow and an insight into these phenomena is of significant importance to many industrial processes. The experimental technique exploited here gives an insight into the dissolution of liquid microdroplets under extensional flow regime. The comparison of our experimental results with ZYM model reveals that dissolution of microdroplets at lower surfactant concentration (10µM) fits the ZYM model at saturation concentration (Cs) value reported in literature (Cs = 15×10⁻³Kg\m³) while for higher surfactant concentration (10mM) which is also above the critical micelle concentration (CMC) of surfactant (5mM) the data fits ZYM model at (Cs = 45×10⁻³Kg\m³) which is 3X times the value reported in literature. The difference in Cs value from the literature shows enhancement in dissolution rate of sparingly soluble BB microdroplets at surfactant concentrations higher than CMC. Enhancement in the dissolution of sparingly soluble materials is of great importance in pharmaceutical industry. Enhancement in the dissolution of sparingly soluble drugs is a key research area for drug design industry. The experimental method is also advantageous because it is robust and has no mechanical contact with droplets under study are freely suspended in the fluid as compared existing methods used for testing dissolution of drugs. The experiments also give an insight into CMC measurement for surfactants.

Keywords: extensional flow, hydrodynamic trapping, Zhang-Yang-Mao, CMC

Procedia PDF Downloads 320

Authors: Pinar Erturk, Sevde Altuntas, Fatih Buyukserin

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In order to obtain an effective integration between an implant and a bone, implant surfaces should have similar properties to bone tissue surfaces. Especially mimicry of the chemical, mechanical and topographic properties of the implant to the bone is crucial for fast and effective osseointegration. Titanium-based biomaterials are more preferred in clinical use, and there are studies of coating these implants with oxide layers that have chemical/nanotopographic properties stimulating cell interactions for enhanced osseointegration. There are low success rates of current implantations, especially in craniofacial implant applications, which are large and vital zones, and the oxide layer coating increases bone-implant integration providing long-lasting implants without requiring revision surgery. Our aim in this study is to examine bone-cell behavior on titanium implants with an aluminum oxide layer (AAO) on effective osseointegration potential in the deformation of large zones with difficult spontaneous healing. In our study, aluminum layer coated titanium surfaces were anodized in sulfuric, phosphoric, and oxalic acid, which are the most common used AAO anodization electrolytes. After morphologic, chemical, and mechanical tests on AAO coated Ti substrates, viability, adhesion, and mineralization of adult bone cells on these substrates were analyzed. Besides with atomic layer deposition (ALD) as a sensitive and conformal technique, these surfaces were coated with pure alumina (5 nm); thus, cell studies were performed on ALD-coated nanoporous oxide layers with suppressed ionic content too. Lastly, in order to investigate the effect of the topography on the cell behavior, flat non-porous alumina layers on silicon wafers formed by ALD were compared with the porous ones. Cell viability ratio was similar between anodized surfaces, but pure alumina coated titanium and anodized surfaces showed a higher viability ratio compared to bare titanium and bare anodized ones. Alumina coated titanium surfaces, which anodized in phosphoric acid, showed significantly different mineralization ratios after 21 days over other bare titanium and titanium surfaces which anodized in other electrolytes. Bare titanium was the second surface that had the highest mineralization ratio. Otherwise, titanium, which is anodized in oxalic acid electrolyte, demonstrated the lowest mineralization. No significant difference was shown between bare titanium and anodized surfaces except AAO titanium surface anodized in phosphoric acid. Currently, osteogenic activities of these cells on the genetic level are investigated by quantitative real-time polymerase chain reaction (qRT-PCR) analysis results of RUNX-2, VEGF, OPG, and osteopontin genes. Also, as a result of the activities of the genes mentioned before, Western Blot will be used for protein detection. Acknowledgment: The project is supported by The Scientific and Technological Research Council of Turkey.

Keywords: alumina, craniofacial implant, MG-63 cell line, osseointegration, oxalic acid, phosphoric acid, sulphuric acid, titanium

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Authors: Gizem Kodak, Alper Unal, Birsen Koldemir, Tayfun Acarer

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Turkish Straits System which consists of Istanbul Strait (Bosphorus), Canakkale Strait (Dardanelles) and the Marmara Sea has a strategical location on international maritime as it is a unique waterway between the Mediterranean Sea, Black Sea and the Aegean Sea. Thus, this area has great importance since it is the only waterway between Black Sea countries and the rest of the World. Turkish Straits System has dangerous environmental factors hosts more vessel every day through developing World trade and this situation results in expanding accident risks day by day. Today, a lot of precautions have been taken to ensure safe navigation and to prevent maritime accidents, and international standards are followed to avoid maritime accidents. Despite this, the environmental factors that affect this area, trigger the maritime accidents and threaten the vessels with new accidents risks in different months with different hazards. This descriptive study consists of temporal and spatial analyses of environmental factors causing maritime accidents. This study also aims at contributing to safety navigation including monthly and regionally characteristics of variables. In this context, two different data sets are created consisting of environmental factors and accidents. This descriptive study on the accidents between 2001 and 2017 the mentioned region also studies the months and places of the accidents with environmental factor variables. Environmental factor variables are categorized as dynamic and static factors. Dynamic factors are appointed as meteorological and oceanographical while static factors are appointed as geological factors that threaten safety navigation with geometrical restricts. The variables that form dynamic factors are approached meteorological as wind direction, wind speed, wave altitude and visibility. The circulations and properties of the water mass on the system are studied as oceanographical properties. At the end of the study, the efficient meteorological and oceanographical parameters on the region are presented monthly and regionally. By this way, we acquired the monthly, seasonal and regional distributions of the accidents. Upon the analyses that are done; The Turkish Straits System that connects the Black Sea countries with the other countries and which is one of the most important parts of the world trade; is analyzed on temporal and spatial dimensions on the reasons of the accidents and have been presented as environmental factor dynamics causing maritime accidents.

Keywords: descriptive study, environmental factors, maritime accidents, statistics

Procedia PDF Downloads 168

Authors: Sengul Celik, Alper Ketenci

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In Turkish Constitution about health care in Article 56, it is said that: everyone has the right to live in a healthy and balanced environment. It is the duty of the state and citizens to improve the environment, protect environmental health, and prevent environmental pollution. The state ensures that everyone lives their lives in physical and mental health; it organizes the planning and service of health institutions from a single source in order to realize cooperation by increasing savings and efficiency in human and substance power. The state fulfills this task by utilizing and supervising health and social institutions in the public and private sectors. General health insurance can be established by law for the widespread delivery of health services. To have health care is one of the basic rights of patients. After the coupe attempt in July 2016, the Government of Turkey has announced a state of emergency and issued lots of emergency decrees. By these emergency decrees, lots of people were dismissed from their jobs and lost their some basic social rights. The violations occur in social life. One of the most common observations is the discrimination by government in health care system. This study aims to put forward the violation of human rights in health care system in Turkey due to their discriminated position by an emergency decree. The study is a case study that is based on nine interviews with the people or relatives of people who lost their jobs by an emergency decree in Turkey. In this study, no personally identifiable information was obtained for the safety of individuals. Also no distinctive questions regarding the identity of individuals were asked. The interviews are obtained through internet call applications. The data were analyzed through the requirements of regular health care system in Turkey. The interviews expose that the people or the relatives of people lost their right to have regular health care. They have to pay extra amount both in clinical services and in medication treatment. The patient right to quality medical care without prejudice is violated. It was assessed that the people who are involved in emergency decree and their relatives are discriminated by government and deprived of regular medical care and supervision. Although international legal arrangements and legal responsibilities of the state have been put forward by Article 56, they are violated in practice. To prevent these kinds of violations, some measures should be taken against the deprivation in health care system especially towards the discriminated people by an emergency decree.

Keywords: emergency decree in Turkey, health care, discriminated people, patients rights

Procedia PDF Downloads 84

Authors: Alper Tolga Kumtepe, Erdem Erdogdu, M. Recep Okur, Eda Kaypak, Ozlem Kaya, Serap Ugur, Deniz Dincer, Hakan Yildirim

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Interaction is one of the most important components of open and distance learning. According to Moore, who proposed one of the keystones on interaction types, there are three basic types of interaction: learner-teacher, learner-content, and learner-learner. From these interaction types, learner-content interaction, without doubt, can be identified as the most fundamental one on which all education is based. Efficacy, efficiency, and attraction of open and distance learning systems can be achieved by the practice of effective learner-content interaction. With the development of new technologies, interactive e-learning materials have been commonly used as a resource in open and distance learning, along with the printed books. The intellectual engagement of the learners with the content that is course materials may also affect their satisfaction for the open and distance learning practices in general. Learner satisfaction holds an important place in open and distance learning since it will eventually contribute to the achievement of learning outcomes. Using the learner-content interaction activities in course materials, Anadolu University, by its Open Education system, tries to involve learners in deep and meaningful learning practices. Especially, during the e-learning material design and production processes, identifying appropriate learner-content interaction activities within the context of learning outcomes holds a big importance. Considering the lack of studies adopting this approach, as well as its being a study on the use of e-learning materials in Open Education system, this research holds a big value in open and distance learning literature. In this respect, the present study aimed to investigate a) which learner-content interaction activities included in interactive courses are the most effective in learners’ achievement of verbal information learning outcomes and b) to what extent distance learners are satisfied with these learner-content interaction activities. For this study, the quasi-experimental research design was adopted. The 120 participants of the study were from Anadolu University Open Education Faculty students living in Eskişehir. The students were divided into 6 groups randomly. While 5 of these groups received different learner-content interaction activities as a part of the experiment, the other group served as the control group. The data were collected mainly through two instruments: pre-test and post-test. In addition to those tests, learners’ perceived learning was assessed with an item at the end of the program. The data collected from pre-test and post-test were analyzed by ANOVA, and in the light of the findings of this approximately 24-month study, suggestions for the further design of e-learning materials within the context of learner-content interaction activities will be provided at the conference. The current study is planned to be an antecedent for the following studies that will examine the effects of activities on other learning domains.

Keywords: interaction, distance education, interactivity, online courses

Procedia PDF Downloads 164

Authors: Fatih Gundogan, Fatih Kafali, Abdullah Karadag, Alper Baloglu, Ersoy Pehlivan, Mustafa Eruyar, Osman Bayram, Orhan Karademiroglu, Wasim Shoman

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Nowadays many cities around the world are investing their efforts and resources for the purpose of facilitating their citizen’s life and making cities more livable and sustainable by implementing newly emerged phenomena of smart city. For this purpose, related research institutions prepare and publish smart city indices or benchmarking reports aiming to measure the city’s current ‘smartness’ status. Several functional domains, various indicators along different selection and calculation methods are found within such indices and reports. The selection criteria varied for each institution resulting in inconsistency in the ranking and evaluating. This research aims to evaluate the impact of selecting such functional domains, indicators and calculation methods which may cause change in the rank. For that, six functional domains, i.e. Environment, Mobility, Economy, People, Living and governance, were selected covering 19 focus areas and 41 sub-focus (variable) areas. 60 out of 191 indicators were also selected according to several criteria. These were identified as a result of extensive literature review for 13 well known global indices and research and the ISO 37120 standards of sustainable development of communities. The values of the identified indicators were obtained from reliable sources for ten cities. The values of each indicator for the selected cities were normalized and standardized to objectively investigate the impact of the chosen indicators. Moreover, the effect of choosing an integration method to represent the values of indicators for each city is investigated by comparing the results of two of the most used methods i.e. geometric aggregation and fuzzy logic. The essence of these methods is assigning a weight to each indicator its relative significance. However, both methods resulted in different weights for the same indicator. As a result of this study, the alternation in city ranking resulting from each method was investigated and discussed separately. Generally, each method illustrated different ranking for the selected cities. However, it was observed that within certain functional areas the rank remained unchanged in both integration method. Based on the results of the study, it is recommended utilizing a common platform and method to objectively evaluate cities around the world. The common method should provide policymakers proper tools to evaluate their decisions and investments relative to other cities. Moreover, for smart cities indices, at least 481 different indicators were found, which is an immense number of indicators to be considered, especially for a smart city index. Further works should be devoted to finding mutual indicators representing the index purpose globally and objectively.

Keywords: functional domain, urban city index, indicator, smart city

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Authors: Alper T. Celebi, Ali Beskok

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Electroosmotic (EO) slip flows in nanochannels are investigated using non-equilibrium molecular dynamics (MD) simulations, and the results are compared with analytical solution of Poisson-Boltzmann and Stokes (PB-S) equations with slip contribution. The ultimate objective of this study is to show that well-known continuum flow model can accurately predict the EO velocity profiles in nanochannels using the slip lengths and apparent viscosities obtained from force-driven flow simulations performed at various liquid-wall interaction strengths. EO flow of aqueous NaCl solution in silicon nanochannels are simulated under realistic electrochemical conditions within the validity region of Poisson-Boltzmann theory. A physical surface charge density is determined for nanochannels based on dissociations of silanol functional groups on channel surfaces at known salt concentration, temperature and local pH. First, we present results of density profiles and ion distributions by equilibrium MD simulations, ensuring that the desired thermodynamic state and ionic conditions are satisfied. Next, force-driven nanochannel flow simulations are performed to predict the apparent viscosity of ionic solution between charged surfaces and slip lengths. Parabolic velocity profiles obtained from force-driven flow simulations are fitted to a second-order polynomial equation, where viscosity and slip lengths are quantified by comparing the coefficients of the fitted equation with continuum flow model. Presence of charged surface increases the viscosity of ionic solution while the velocity-slip at wall decreases. Afterwards, EO flow simulations are carried out under uniform electric field for different liquid-wall interaction strengths. Velocity profiles present finite slips near walls, followed with a conventional viscous flow profile in the electrical double layer that reaches a bulk flow region in the center of the channel. The EO flow enhances with increased slip at the walls, which depends on wall-liquid interaction strength and the surface charge. MD velocity profiles are compared with the predictions from analytical solutions of the slip modified PB-S equation, where the slip length and apparent viscosity values are obtained from force-driven flow simulations in charged silicon nano-channels. Our MD results show good agreements with the analytical solutions at various slip conditions, verifying the validity of PB-S equation in nanochannels as small as 3.5 nm. In addition, the continuum model normalizes slip length with the Debye length instead of the channel height, which implies that enhancement in EO flows is independent of the channel height. Further MD simulations performed at different channel heights also shows that the flow enhancement due to slip is independent of the channel height. This is important because slip enhanced EO flow is observable even in micro-channels experiments by using a hydrophobic channel with large slip and high conductivity solutions with small Debye length. The present study provides an advanced understanding of EO flows in nanochannels. Correct characterization of nanoscale EO slip flow is crucial to discover the extent of well-known continuum models, which is required for various applications spanning from ion separation to drug delivery and bio-fluidic analysis.

Keywords: electroosmotic flow, molecular dynamics, slip length, velocity-slip

Procedia PDF Downloads 119

Authors: Dilek Ozturk, Narin Ozturk, Zeliha Pala Kara, Engin Kaptan, Serap Sancar Bas, Nurten Ozsoy, Alper Okyar

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Most physiological processes oscillate in a rhythmic manner in mammals including metabolism and energy homeostasis, locomotor activity, hormone secretion, immune and endocrine system functions. Endocrine body rhythms are tightly regulated by the circadian timing system. The hypothalamic-pituitary-thyroid (HPT) axis is under circadian control at multiple levels from hypothalamus to thyroid gland. Since circadian timing system controls a variety of biological functions in mammals, circadian rhythms of biological functions may modify the drug tolerability/toxicity depending on the dosing time. Selective mTOR (mammalian target of rapamycin) inhibitor everolimus is an immunosuppressant and anticancer agent that is active against many cancers. It was also found to be active in medullary thyroid cancer. The aim of this study was to investigate the dosing time-dependent toxicity of everolimus on the thyroid gland and hormones in mice. Healthy C57BL/6J mice were synchronized with 12h:12h Light-Dark cycle (LD12:12, with Zeitgeber Time 0 – ZT0 – corresponding to Light onset). Everolimus was administered to male (5 mg/kg/day) and female mice (15 mg/kg/day) orally at ZT1-rest period- and ZT13-activity period- for 4 weeks; body weight loss, clinical signs and possible changes in serum thyroid hormone levels (TSH and free T4) were examined. Histological alterations in the thyroid gland were evaluated according to the following criteria: follicular size, colloid density and viscidity, height of the follicular epithelium and the presence of necrotic cells. The statistical significance between differences was analyzed with ANOVA. Study findings included everolimus-related diarrhea, decreased activity, decreased body weight gains, alterations in serum TSH levels, and histopathological changes in thyroid gland. Decreases in mean body weight gains were more evident in mice treated at ZT1 as compared to ZT13 (p < 0.001, for both sexes). Control tissue sections of thyroid glands exhibited well-organized histoarchitecture when compared to everolimus-treated groups. Everolimus caused histopathological alterations in thyroid glands in male (5 mg/kg, slightly) and female mice (15 mg/kg; p < 0.01 for both ZT as compared to their controls) irrespective of dosing-time. TSH levels were slightly decreased upon everolimus treatment at ZT13 in both males and females. Conversely, increases in TSH levels were observed when everolimus treated at ZT1 in both males (5 mg/kg; p < 0.05) and females (15 mg/kg; slightly). No statistically significant alterations in serum free T4 levels were observed. TSH and free T4 is clinically important thyroid hormones since a number of disease states have been linked to alterations in these hormones. Serum free T4 levels within the normal ranges in the presence of abnormal serum TSH levels in everolimus treated mice may suggest subclinical thyroid disease which may have repercussions on the cardiovascular system, as well as on other organs and systems. Our study has revealed the histological damage on thyroid gland induced by subacute everolimus administration, this effect was irrespective of dosing time. However, based on the body weight changes and clinical signs upon everolimus treatment, tolerability for the drug was best following dosing at ZT13 in both male and females. Yet, effects of everolimus on thyroid functions may deserve further studies regarding their clinical importance and chronotoxicity.

Keywords: circadian rhythm, chronotoxicity, everolimus, thyroid gland, thyroid hormones

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Authors: Narin Ozturk, Xiao-Mei Li, Sylvie Giachetti, Francis Levi, Alper Okyar

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P-glycoprotein (P-gp, MDR1, ABCB1) is a transmembrane protein acting as an ATP-dependent efflux pump and functions as a biological barrier by extruding drugs and xenobiotics out of cells in healthy tissues especially in intestines, liver and brain as well as in tumor cells. The circadian timing system controls a variety of biological functions in mammals including xenobiotic metabolism and detoxification, proliferation and cell cycle events, and may affect pharmacokinetics, toxicity and efficacy of drugs. Selective mTOR (mammalian target of rapamycin) inhibitor everolimus is an immunosuppressant and anticancer drug that is active against many cancers, and its pharmacokinetics depend on P-gp. The aim of this study was to investigate the dosing time-dependent toxicity of everolimus with respect to the intestinal P-gp expression rhythms in mdr1a::Luc mice using Real Time-Biolumicorder (RT-BIO) System. Mdr1a::Luc male mice were synchronized with 12 h of Light and 12 h of Dark (LD12:12, with Zeitgeber Time 0 – ZT0 – corresponding Light onset). After 1-week baseline recordings, everolimus (5 mg/kg/day x 14 days) was administered orally at ZT1-resting period- and ZT13-activity period- to mdr1a::Luc mice singly housed in an innovative monitoring device, Real Time-Biolumicorder units which let us monitor real-time and long-term gene expression in freely moving mice. D-luciferin (1.5 mg/mL) was dissolved in drinking water. Mouse intestinal mdr1a::Luc oscillation profile reflecting P-gp gene expression and locomotor activity pattern were recorded every minute with the photomultiplier tube and infrared sensor respectively. General behavior and clinical signs were monitored, and body weight was measured every day as an index of toxicity. Drug-induced body weight change was expressed relative to body weight on the initial treatment day. Statistical significance of differences between groups was validated with ANOVA. Circadian rhythms were validated with Cosinor Analysis. Everolimus toxicity changed as a function of drug timing, which was least following dosing at ZT13, near the onset of the activity span in male mice. Mean body weight loss was nearly twice as large in mice treated with 5 mg/kg everolimus at ZT1 as compared to ZT13 (8.9% vs. 5.4%; ANOVA, p < 0.001). Based on the body weight loss and clinical signs upon everolimus treatment, tolerability for the drug was best following dosing at ZT13. Both rest-activity and mdr1a::Luc expression displayed stable 24-h periodic rhythms before everolimus and in both vehicle-treated controls. Real-time bioluminescence pattern of mdr1a revealed a circadian rhythm with a 24-h period with an acrophase at ZT16 (Cosinor, p < 0.001). Mdr1a expression remained rhythmic in everolimus-treated mice, whereas down-regulation was observed in P-gp expression in 2 of 4 mice. The study identified the circadian pattern of intestinal P-gp expression with an unprecedented precision. The circadian timing depending on the P-gp expression rhythms may play a crucial role in the tolerability/toxicity of everolimus. The circadian changes in mdr1a genes deserve further studies regarding their relevance for in vitro and in vivo chronotolerance of mdr1a-transported anticancer drugs. Chronotherapy with P-gp-effluxed anticancer drugs could then be applied according to their rhythmic patterns in host and tumor to jointly maximize treatment efficacy and minimize toxicity.

Keywords: circadian rhythm, chronotoxicity, everolimus, mdr1a::Luc mice, p-glycoprotein

Procedia PDF Downloads 311